Project Summary/Abstract Young African Americans (AAs) are 3X as likely to have a stroke compared to European Americans (EAs). A major challenge for reducing disparities in stroke amongst young AAs is the poor understanding of molecular mechanisms that facilitate early onset hypertension in healthy, asymptomatic AAs. The long-term goal of the candidate is to establish an independent research career focused on understanding the role of social epigenomics in modulating racially disparate outcomes in cerebrovascular diseases. The objective of this application is to systematically investigate social epigenomic mechanisms associated with aberrant arterial stiffness patterns, which precedes the development of hypertension, in asymptomatic blacks vs whites. Given that adverse experiences are known to mediate epigenetic changes in the vasculature, our central hypotheses are that 1) psychosocial stress is associated with differences in cfPWV between AAs and EAs and that 2) altered expression extracellular matrix-specific miRNAs are associated with cfPWV as a function of differences in psychosocial stress. Three specific aims address these interrelated hypotheses. In Aim 1 (Training-Phase I) we will determine the association between psychosocial stress and arterial stiffness in AA and EA college students. Here, we will correlate arterial stiffness, as measured by carotid-femoral pulse wave velocity with childhood and early adulthood psychosocial stress using validated survey tools. In Aim 2 (Transition to Independence, Phase I/II) we will determine the expression patterns of extracellular matrix-relevant plasma and serum proteins in AA and EA subjects using liquid biopsy samples acquired from college students in Aim 1. We will assess protein levels using ELISA and Western blot assays. In Aim 3 (Independent Aim/Phase II) we will use a bioinformatics approach to identify extracellular vesicle and plasma concentrations of extracellular matrix- relevant microRNAs in AAs and EAs study subjects. Upon successful completion of the proposed research and training, we expect to provide insight on molecular mechanisms that drive premature large artery stiffening in young, healthy AAs race individuals. This contribution is expected to be significant because it will provide potential novel therapeutic avenues for the postponement of hypertension onset in AAs that will help alleviate disparities in stroke incidence and mortality. Our research is innovative in that it seeks to shift this paradigm by focusing on the how the biological embedding of adverse environmental exposures (e.g. abuse, racism) impacts premature large artery stiffness and differential expression of relevant epigenetic biomarkers such as microRNAs. Moreover, it utilizes a transdisciplinary approach to address the clinical problem. The proposed studies will provide a platform for Dr. Buie to gain expertise and training in clinical trial design, implementation and analysis. Moreover, she will become proficient in mixed methods (quantitative and qualitative) research and employing bioinformatic and epigenomic principles for addressing health disparities in stroke.